The overall objective of this research proposal is to elucidate a new pathological mechanism underlying autoimmune diseases such as multiple sclerosis (MS) and to test a new class of therapeutic compounds in models of MS. The proposal is inspired by two lines of recent discoveries: (i) in humans, several genome-wide association studies independently established that c-Rel, the lymphoid and myeloid member of the Rel/nuclear factor-kB (Rel/NF-kB) family, is a risk factor for six autoimmune diseases including MS; (ii) in mice, c-Rel deficiency renders them resistant to autoimmune encephalomyelitis, arthritis, and colitis while having limited impact on infections. We therefore theorized that c-Rel is both a risk factor and a pathogenic factor for human autoimmune diseases and that drugs targeting it should be effective for treating the diseases. To test this theory, we have developed a new class of small molecules that specifically inhibits c-Rel function by preventing its binding to DNA. In mice, these compounds are highly effective in suppressing autoimmune responses and in ameliorating ongoing experimental autoimmune encephalomyelitis, an animal model for MS. The specific goals of this proposal are to elucidate the mechanism(s) through which c-Rel controls autoimmune encephalomyelitis, and to test the theory that inhibition of c-Rel in both inflammatory and regulatory T cells is required to cure autoimmune encephalomyelitis. Specifically, we will test the hypotheses that (i) c-Rel serves as a transcriptional checkpoint of autoimmune encephalomyelitis; (ii) c-Rel controls autoimmune encephalomyelitis in a cell- and gene-specific manner; and (iii) c-Rel blockade diminishes anti- myelin immune responses of multiple sclerosis patients.